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Primer on Core Longevity Concepts

Penning down some learnings from a Longevity Conference…

Epigenetics

  • All nucleated cells have the same DNA sequence. What makes cells different in functionality is which genes they actually express (gene regulation). This is dictated by which transcription factors in the cell are present
  • Another way of regulation is the epigenome - a way to affect the expression of genes by either covalently modifying DNA bases without changing the base sequence, covalently modifying the histone proteins, remodeling chromatin, or regulating non-coding RNA
  • Covalent modifications include methylation, hydroxymethylation, acetylation, etc. - these are just chemical groups or proteins added covalently to the DNA bases or the amino acids making up histones
  • Promoter region: A DNA region located just upstream of a gene. Its job is to provide a binding site for transcription factors, recruit RNA polymerase, and start transcription. If transcription machinery can bind, the gene is expressed. If it cannot bind, the gene is silenced.
  • Chromatin remodeling: Move nucleosomes to expose promoter regions, or position them to block transcription machinery. Hence, DNA becomes more accessible or less accessible for transcription
  • Non-coding RNA regulation: RNA molecules that don’t encode proteins but regulate gene expression. Controls mRNA stability, regulates translation, and can recruit epigenetic modifiers to DNA
  • So, epigenetics affects how DNA is read (by tightening/loosening DNA packaging, recruiting/blocking transcription factors, etc.), not what the DNA sequence is.

DNA Methylation

  • DNA methylation is one of the key epigenetic mechanisms that link gene regulation to aging and longevity.
  • A DNA methylation pattern is the specific map of where methyl groups are attached to DNA across the genome.
  • DNA methylation usually happens at CpG sites (Cytosine - Phosphate - Guanine). In mammals, ~70–80% of CpG cytosines are methylated
  • DNA methylation patterns help maintain cellular identity and genome stability. As those patterns drift with age, cells lose regulation and resilience. Longevity is associated with slower, more stable methylation change.
  • Highly methylated promoter regions will switch off a gene (i.e. gene is no longer expressed). Many promoters contains CpG islands which are normally unmethylated. When they become methylated, some transcription factors cannot recognize the methylated binding sites, and transcription initiation fails.

Epigenetic Clocks

  • Epigenetic clocks are biological age predictors based on patterns of DNA methylation
    • E.g. Horvath’s clock which calculates age acceleration (diff between biological & chornological age), AltumAge (deep-learning model that predicts biological age from DNA methylation data across multiple tissue types), etc..
  • They help determine whether certain therapies are slowing biological aging (i.e. is the longevity therapy effective?)
  • If epigenetic age > chronological age, they often show faster biological aging, and more age-related diseases

Tissue-specific ageing trajectories

  • The idea that different tissues in the same body age at different speeds and in different ways over time
  • Biological age isn’t just a single number… one might have young cardiovascular tissue, but an older immune system

Pan-Tissue Clocks

  • Pan-tissue means across many different tissues, not limited to one specific tissue type.
  • A pan-tissue clock is an epigenetic clock that works across many different tissue types, rather than being specific to one tissue like blood or skin
  • They were developed to identify ageing signals shared across many tissues, allowing us to measure systemic biological ageing.
  • This is important because we often want a general biological age measurement
  • Because tissues age differently, researchers use
    1. Pan-tissue clocks: Estimate overall biological age
    2. Tissue-specific clocks: Measure ageing in particular organs

NAD+ metabolism

  • NAD+ (nicotinamide adenine dinucleotide) is a small molecule found in every living cell. Can be thought of as cellular currency that your body constantly earns, spends, and recycles.
  • NAD+ has 2 big jobs. a) Energy production (convert food into ATP, the cell’s energy). b) cell maintenance & repair (fuels enzymes involved in DNA repair, Stress resistance, Inflammation Control, Gene Regulation, etc.)
  • NAD+ levels decline with age… as we get older, NAD+ production drops, and NAD+ consumption increases (due to chronic inflammation, DNA damage, stress)
  • In animal studies, increasing NAD⁺+ levels has been shown to improve metabolic health, extend lifespan in some species

Lifespan vs Healthspan

  • Lifespan: How long you live - total years from birth to death
  • Healthspan: How well you live - the number of years you’re physically, mentally, and functionally healthy
  • e.g. If someone lives to 85 but develops serious chronic disease at 65, their healthspan is 65 years.

Translational gap

  • We know a lot about how to slow aging in the lab, but very little of it reliably helps humans yet
  • E.g. Interventions work on mice, roundworms, etc… but it isn’t proven on humans…

Senescent-cell-based Therapies

  • Senolytic therapies eliminates senescent cells, reducing chronic inflammation linked to aging.
  • However, there are second-order downsides - senescence acts as a protective mechanism against cancer, spread of damaged DNA
  • Senolytic therapies aim to target chronic senescent cells (long-term acculumation that drives aging) without interfering with **acute senescent cells (**temporary beneficial ones)

Published by:

Alex